Collagenase activities have been implicated in ulceration and perforation of diseased, wounded and alkali-burned corneas. The purpose of this research is to devise chemical means for the control of collagenolytic activity of afflicted eyes by means of active-site- specific covalent modifications of corneal collagenase. The design of such inhibitors is projected from present knowledge of collagenases of Clostridium histolyticum and Rana catesbianna. The inhibitors to be studied will include both low molecular weight derivatives of imidazoles and peptides as well as macromolecular agents derived from collagen fragmented by collagenase. Potential inhibitors will be tested in vitro for their ability to covalently inhibit isolated collagenases using kinetic and isotopic methods. The most promising of these will be tested further on corneal tissue explants and finally by direct topical application to alkali-burned corneas of rabbits. The results of these studies are expected to open the way for effective prevention of secondary corneal loss due to ulceration and perforation after eye injury, disease or surgery.